Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 7 3 2024 09 22 95 98 Amirhossein Hessami Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran Keyvan Heydari Gastrointestinal Cancer Research Center, Non-Communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran; Aref Hosseini Non-communicable Disease Institute, Mazandaran University of Medical Sciences, Sari, Iran Negar Asghari Department of Medical Laboratory, Golestan University of Medical Sciences, Gorgan, Iran 2025 01 09 2025 02 16 A novel coronavirus disease (COVID-19) have raised in Whuan in December 2019. This disease kept spreading rapidly until World Health Organization have declared a pandemic on COVID-19. Despite all the efforts made there are no definite treatments for this disease. Recent papers on pathophysiology of COVID-19 have shown possible mechanism of T-Cell exhaustion caused by virus is responsible for lymphopenia observed in these patients. PD-1/PD-L1 have a major role in T-Cell exhaustion so we have proposed targeting PD-1/PD-L1 using anti-PD-1/PD-L1 agent. Using anti-PD-1/PD-L1 agents including Pembrolizumab and Nivolumab could potentially decrease T-Cell exhaustion and increases survival of COVID-19 patients. In order to overcome the shortcoming of this approach we have proposed using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) which can be highly efficient in targeting PD-1/PD-L1. Using CRISPR/Cas9 in this regard could be more efficient, feasible and economical and potentially lower side effects. In conclusion targeting PD-1/PD-L1 through approved medications or CRISPR/Cas9, in order to block their interactions, may remarkably prevent the cytotoxic lymphocytes functional exhaustion, especially CD8+ T-cells and help to decrease the mortality rate in COVID-19 patients. In addition, to evaluate the clinical outcome of using anti-PD-1/PD-L1 agents or CRISPR/Cas9 system in COVID-19 patients, it is recommended to measure lymphocyte, CD8+ T-cells, NK cells and total T-cells count. https://igj.tums.ac.ir/index.php/igj/article/view/165 https://igj.tums.ac.ir/index.php/igj/article/download/165/150